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Chromatin Remodelers as Players and Drivers in Pathological States
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Chromatin Remodelers as Players and Drivers in Pathological States

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 5061

Special Issue Editor

Dr. Matteo De March

E-Mail Website
Guest Editor
Laboratory of Environmental and Life Sciences, University of Nova Gorica, Vipavska Cesta 13, P.O. Box 301, SI-5000 Nova Gorica, Slovenia
Interests: protein structure and function; protein–DNA complexes; chromatin remodellers; DNA replication; DNA damage response; cancer; cancer diagnosis

Special Issue Information

Dear Colleagues,

I would like to draw our attention to chromatin remodelers, particularly their role and contribution to the development of pathological states, such as cancer.

Indeed, it is known that proteins such as INO80, CHD7, or RSF1 participate in the regulation of oncogenes at different levels, mainly through the recruitment of other mediators and, therefore, their overexpression in different human tissues. On the other hand, some of them are considered tumor suppressors, such as HLTF or ZRANB3, since they bypass DNA damage or stimulate damage repair. Of note, SMARCAL1 from the same SNF2 family was recently characterized as a dual agent in cancer cells, underscoring its multipurpose and critical involvement in maintaining genome stability and regulating the cell cycle.

While this information goes a long way toward understanding how these proteins are regulated or actively regulate disease processes, there is still much to discover. The lack of sufficient structural and functional data and information at the cellular level impedes our understanding of their mechanistic effects on the development of this pathology.

This Special Issue aims to broaden current knowledge on this topic and constitutes an opportunity to gather the latest results obtained by experts in the field, which could potentially aid the design of new diagnostic and therapeutic tools.

Dr. Matteo De March
Guest Editor

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Keywords

  • protein structure/function
  • chromatin remodelers
  • DNA repair
  • oncogene/oncosuppressor
  • cancer

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Published Papers (3 papers)

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18 pages, 4994 KiB  
Article
CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models
by Rita Sala, Hector Esquer, Timothy Kellett, Sophia Clune, Paul Awolade, Laura A. Pike, Qiong Zhou, Wells A. Messersmith and Daniel V. LaBarbera
Int. J. Mol. Sci. 2024, 25(23), 13160; https://doi.org/10.3390/ijms252313160 - 7 Dec 2024
Cited by 1 | Viewed by 1286
Abstract
Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin [...] Read more.
Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression. We show that an inhibitor of CHD1L, OTI-611, when combined with chemotherapy significantly increases DNA damage in CRC cell lines. OTI-611 also synergizes with SN-38, 5-FU, and oxaliplatin in killing CRC tumor organoids. We also demonstrate that, as in breast cancer, OTI-611 traps CHD1L, PARP1, and PARP2 onto chromatin. The entrapment of CHD1L causes the deprotection of PAR chains in the nucleus, ultimately resulting in cell death by CHD1Li-mediated PARthanatos, as measured by AIF translocation to the nucleus. Finally, the combination of low doses of OTI-611 with irinotecan significantly reduces tumor volume and extends survival in CRC xenograft mouse models compared to irinotecan alone. The combination of standard of care chemotherapy drugs with CHD1Li represents a promising advancement in future therapeutic strategies for CRC and other cancers driven by CHD1L. Full article
(This article belongs to the Special Issue Chromatin Remodelers as Players and Drivers in Pathological States)
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13 pages, 2983 KiB  
Article
Overexpression of Chromatin Remodeling Factor SRG3 Down-Regulates IL1β-Expressing M1 Macrophages and IL17-Producing T Cells in Adipose Tissues
by Jungmin Jeon, Sung Won Lee, Hyun Jung Park, Yun Hoo Park, Tae-Cheol Kim, Sujin Lee, Seyeong Lee, Luc Van Kaer and Seokmann Hong
Int. J. Mol. Sci. 2024, 25(21), 11681; https://doi.org/10.3390/ijms252111681 - 30 Oct 2024
Cited by 1 | Viewed by 1006
Abstract
The SWItch3-related gene (SRG3) is a core component of ATP-dependent SWI/SNF complexes, which are crucial for regulating immune cell development and function (e.g., macrophages and CD4+ T cells), embryonic development, and non-immune cell differentiation. Notably, SRG3 overexpression has been shown to polarize [...] Read more.
The SWItch3-related gene (SRG3) is a core component of ATP-dependent SWI/SNF complexes, which are crucial for regulating immune cell development and function (e.g., macrophages and CD4+ T cells), embryonic development, and non-immune cell differentiation. Notably, SRG3 overexpression has been shown to polarize macrophages in the central nervous system toward an anti-inflammatory M2 phenotype, thereby protecting against the development of experimental autoimmune encephalomyelitis in mice. However, the effect of SRG3 on immune responses in adipose tissues remains unclear. To address this issue, we examined the cellularity and inflammatory status of adipose tissue in B10.PL mice overexpressing the SRG3 gene under the ubiquitous β-actin promoter (SRG3β-actin). Interestingly, SRG3 overexpression significantly reduced adipocyte size in both white and brown adipose tissues, without affecting the overall adipose tissue weight. Such phenotypic effects might be associated with the improved glucose tolerance observed in SRG3β-actin B10.PL mice. Moreover, we found that SRG3 overexpression down-regulates IL1β-expressing M1 macrophages, leading to a significant decrease in the M1/M2 macrophage ratio. Additionally, SRG3β-actin B10.PL mice showed a dramatic reduction in neutrophils as well as IL1β- and IL17-producing T cells in adipose tissues. Taken together, our results indicate that SRG3 plays a vital role in maintaining immune homeostasis within adipose tissues. Full article
(This article belongs to the Special Issue Chromatin Remodelers as Players and Drivers in Pathological States)
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22 pages, 6276 KiB  
Article
CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos
by Rita Sala, Hector Esquer, Timothy Kellett, Jeffrey T. Kearns, Paul Awolade, Qiong Zhou and Daniel V. LaBarbera
Int. J. Mol. Sci. 2024, 25(16), 8590; https://doi.org/10.3390/ijms25168590 - 6 Aug 2024
Cited by 2 | Viewed by 2037
Abstract
The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological [...] Read more.
The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611. Cytotoxicity as a single agent or in combination with standard-of-care treatments was assessed in tumor organoids. Immunofluorescence was used to assess the translocation of PAR and AIF to the cytoplasm or the nucleus and to study markers of DNA damage or apoptosis. Trapping of PARP1/2 or CHD1L onto chromatin was also assessed by in situ subcellular fractionation and immunofluorescence and validated by Western blot. We show that the inhibition of CHD1L’s ATPase activity by OTI-611 is cytotoxic to triple-negative breast cancer tumor organoids and synergizes with PARPi and chemotherapy independently of the BRCA mutation status. The inhibition of the remodeling function blocks the phosphorylation of H2AX, traps CHD1L on chromatin, and leaves PAR chains on PARP1/2 open for hydrolysis. PAR hydrolysis traps PARP1/2 at DNA damage sites and mediates PAR translocation to the cytoplasm, release of AIF from the mitochondria, and induction of PARthanatos. The targeted inhibition of CHD1L’s oncogenic function by OTI-611 signifies an innovative therapeutic strategy for breast cancer and other cancers. This approach capitalizes on CHD1L-mediated DNA repair and cell survival vulnerabilities, thereby creating synergy with standard-of-care therapies Full article
(This article belongs to the Special Issue Chromatin Remodelers as Players and Drivers in Pathological States)
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